The marine natural products ceratamine A and B, isolated from the New Guinean sponge Pseudoceratina sp., have been shown to possess antimitotic activity in a cell-based assay. These unusual heterocyclic compounds and their analogs join a large family of marine natural products that exhibit antimitotic activity, such as by arresting cells in mitosis, or by stimulating microtubule polymerization in the absence of normally associated proteins. The ceratamines do not compete with taxol for binding to β-tubulin, whereas taxol, the epothilones, discodermolide, and the eleuthesides bind to a common site, which itself is distinct from the binding site of the Vinca alkaloids. Thus, the ceratamines may exhibit a unique spectrum of antitumor activity.
The ceratamines possess an unusual imidazo[4,5-d]azepine ring system that presumably results from the oxidative coupling of a brominated tyrosine and a histidine. Dibromotyrosine-containing natural products are typical of sponges of the order Verongida, which includes the genus Pseudoceratina, and many such metabolites possess interesting biological activity.
U.S. Patent Application Publication 2008/0255090 by Andersen et al. discloses various possible synthetic routes to ceratamines A and B and analogs thereof. The key steps of these synthetic routes rely on a ring-closing olefin metathesis reaction to form the necessary ring structure. However, none of the synthetic routes proposed by Andersen et al. provide a direct pathway from a functionalized aminohydroazepinone skeleton comprising an aminoimidazole ring to the imidazo[4,5-d]azepine ring system of the ceratamines and their analogs.
As a result of the low natural-abundance of ceratamines, typical for sponge-derived secondary metabolites, any preclinical studies of the ceratamines will rely on the availability of usable and significant quantities of synthetic material. Therefore, there exists a strong need for direct and efficient synthetic routes to ceratamines and their analogs in appreciable yields.